Although high-altitude pulmonary edema has been the topic of research activity for a number of years, the basic mechanisms contributing to its formation remain incompletely understood. As a prototypical hypoxia- related lung injury, this condition is of interest because of its potential relationship to other conditions associated with hypoxia and lung injury, including adult respiratory distress syndrome (ARDS). In this proposal, we will present recent evidence suggesting that a stimulus directed at the epithelium (viral infection) may alter the response of the pulmonary vasculature to a second stimulus (hypoxia) and promote the formation of pulmonary edema. We will also present evidence that the effects of viral infection and hypoxia in the lung are mediated at least in part via the actions of the potent vasoconstrictor peptide, endothelin. We propose investigations testing the hypothesis that viral infections promote pulmonary edema formation in the hypoxic lung by altering the production of endothelin peptide and the expression of its receptors. Specifically, the aims of the proposed studies are: 1) to identify the molecular mechanisms by which viral infection augments hypoxia- induced increases in lung endothelin content by measuring expression of key molecules responsible for endothelin production and clearance from the lung; 2) to test the hypothesis that the combination of viral infection and hypoxia promotes pulmonary edema formation via an altered balance between ETA and ETB receptor populations, by using pharmacologic ET receptor antagonists as well as genetically altered animals; and 3) to identify using cell culture techniques the specific lung cell populations in which viral infection and hypoxia act to alter the expression of endothelin and its receptors, and to identify the mediators of those effects. The proposed research will better define the effects of viral respiratory infections and hypoxia on endothelin and its receptors in the lung, and may lead to new therapeutic avenues for acute lung injury, as well as for altitude-related illness.